Unraveling How Dysfunction of the Microglial Gene TREM2 Increases Risk for Alzheimer's Disease

A heterozygous single amino acid change in the TREM2 gene significantly increases risk for developing late-onset Alzheimer’s Disease (AD). In the brain, Trem2 is uniquely expressed by microglia, strongly implicating microglia in AD pathogenesis. Trem2 is a receptor with numerous ligands and pleiotropic functions ranging from phagocytosis to inflammation and synapse pruning. There has been a significant amount of research on the consequences of Trem2 deficiency in amyloid mouse models. Trem2-deficient mice exhibit reduced microglial clustering around amyloid-beta plaques and reduced levels of inflammatory transcripts. The consequence of Trem2 deficiency in the context of tau pathology, on the other hand, is not well understood. To address this gap, we investigated the effects of Trem2 haploinsufficiency and deficiency on microglial function in the healthy brain and in the context of tauopathy. We found that removing one copy of Trem2 significantly impaired microglia’s ability to respond to injury in vivo to a greater extent than removing both copies of Trem2. Moreover, Trem2 haploinsufficient mice exhibited an increase in tau load, whereas tau load in Trem2 deficient mice was unimpacted or slightly reduced. The increase in tau load in Trem2 haploinsufficient mice correlated with increased levels of pro-inflammatory transcripts and neurodegeneration. Trem2 deficient mice, on the other hand, exhibited reduced levels of pro-inflammatory transcripts and less neurodegeneration. To determine how a single amino acid change in TREM2 increases risk for AD, we used CRISPR to generate two novel mouse models expressing one copy of wild-type or R47H human TREM2 (R47H-hTREM2) driven by the endogenous mouse Trem2 promoter. We found that R47H-hTREM2 caused aberrant hippocampal synaptic transmission and impaired spatial memory. In the context of tauopathy, it exacerbated spatial learning and memory as well, and resulted in higher levels of pro-inflammatory and disease-associated microglial transcripts. Moreover, R47H-hTREM2 microglia caused transcriptional changes in neurons and oligodendrocytes, pertaining to metabolism and oxidative phosphorylation. Lastly, there was significant overlap between our R47H-hTREM2 mouse model and AD patients with the R47H mutation. The most significant overlap was in oligodendrocyte transcripts related to mitochondrial dysfunction and oxidative phosphorylation. In sum, the work highlighted in this dissertation highlights how losing one copy of a gene can be more detrimental than losing both copies and how a single amino acid change in one cell type in the brain can have widespread non-cell autonomous ramifications resulting in cognitive deficits. Hopefully, the pathways highlighted in this work can help guide the development of therapeutic strategies targeted at microglial dysfunction in AD.